Many years preclinical and clinical anatomic, pharmacologic, and physiologic studies suggest that SP- and opioid-expressing neurons produce opposite biological effects at the spinal level, i.e., nociception and antinociception, respectively. However, in certain circumstances intrathecally administered SP is capable of reinforcing of spinal morphine analgesia and may therefore function as an opioid adjuvant in vivo. The SP dose-response curve of spinally administered SP follows a bell-shaped or inverted-U configuration, permitting pharmacological dissociation of opioid-potentiating and analgesic properties of SP from traditional hyperalgesic effects seen at significantly higher concentrations. This analgesic effect is blocked by naloxone but unaffected by transection of the spinal cord, thus demonstrating the lack of supraspinal modulation. The present report briefly describes both reinforcing and opposing interactions between multiple opioid systems and substance P at the spinal level. We propose that a likely mechanism underlying SP-mediated enhancement of opioid analgesia is the ability of SP to release endogenous opioid peptides within the local spinal cord environment.